c‐Jun NH₂‐terminal kinase mediates interleukin‐1β‐induced inhibition of lacrimal gland secretion

Abstract

Sjö gren's syndrome, an inflammatory disease affecting the lacrimal and salivary glands, is the leading cause of aqueous tear-deficient type of dry eye. We previously showed that interleukin-1b (IL-1b) protein is up regulated in the lacrimal gland of a murine model of Sjö gren's syndrome and that exogenous addition of this cytokine inhibits neurotransmitter release and lacrimal gland protein secretion. In the present study we investigated the role of c-Jun NH 2 -terminal kinase (JNK) in IL-1b-mediated inhibition of lacrimal gland secretion and tear production. In vitro, IL-1b induced a time-dependent activation of JNK with a maximum 7.5-fold at 30 min. SP600125, a JNK inhibitor, inhibited, in a concentrationdependent manner, IL-1b-induced activation of JNK with a maximum of 87% at 10 )4 M. In vivo, IL-1b stimulated JNK and the expression of the inducible isoform of nitric oxide synthase (iNOS). IL-1b inhibited high KCl and adrenergic agonist induced protein secretion by 85% and 66%, respectively. SP600125 alleviated the inhibitory effect of IL-1b on KCl-and agonist-induced protein secretion by 79% and 47%, respectively, and completely blocked the expression of iNOS. Treatment for 7 days with SP600125 increased tear production in a murine model of Sjö gren's syndrome dry eye. We conclude that JNK plays a pivotal role in IL-1b-mediated inhibition of lacrimal gland secretion and subsequent dry eye.

Identification and Characterization of a Novel Class of c-Jun N-terminal Kinase Inhibitors

“…When mice were dosed with 12.5 and 30 mg/kg IQ-1S i.p., the serum exposure of the compound was also good, with AUC 0-12h values of 2.9 and 7.4 M ⅐ h Ϫ1 , respectively. On the basis of these data, the IC 50 and K d values for in vitro activity of IQ-1S (Tables 1, 2, and 4), and the published doses used for in vivo multiple-dose application of SP600125 (25-30 mg/kg, daily; Han et al, 2001;Zoukhri et al, 2006), we split the total daily dose for SP600125 and IQ-1S into two doses of 12.5 mg/kg. Indeed, splitting the total daily dose has been reported to be more effective than the same dose given once daily (Albert et al, 2006).…”

p38 Mitogen-activated protein kinase modulates exocrine secretion in rabbit lacrimal gland

“…The activation of p38 in epithelial cells of exocrine tissues has been shown to modulate cell differentiation [11] and apoptosis [12], and mediate inflammatory responses [13]. To our knowledge, no previous studies of p38 function in the LG have been conducted other than for the use as a control for specificity of an inhibitor for another MAPK [14]. This study reveals a new function of the actions of p38 where it regulates exocrine secretion.…”

“…1). Several studies have been performed investigating the role of MAPKs in lacrimal secretion, most of them regarding p42/44 [5,[15][16][17], but also c-Jun N-terminal kinase (JNK) [14]. In rat LG, Cch-induced phosphorylation of p42/44 inhibits secretion [5,17].…”

Modulation of c-Jun NH<sub>2</sub>-Terminal (JNK) by Cholinergic Autoantibodies from Patients with Sjögren’s Syndrome

“…Furthermore, the reason why pSS IgG activated iNOS independent of an increase in intracellular calcium concentration was because this isoform could produce large amounts of NO for extended periods of time, far exceeding the levels generated by the constitutive isoforms in the submandibular gland [48]. Also, it has been documented that JNK regulates iNOS expression [49], it is likely that JNK mediates IL-1β-induced expression of iNOS in the lachrymal gland, which leads to inhibition of neural-as well as agonist-induced protein secretion [50].…”